Basic heterocyclic ethers



ni ted States Patent BASIC HETEROCYCLIC ETHERS Norbert Steiger, Nufley,N. J., assignor to Hoffmanngm Roche Inc., Nufley, N. J., a corporationof New ersey No Drawing. Application June 14, 1954, Serial No. 436,717

8 Claims. (Cl. 260--279) This invention relates to novel chemicalcompounds and to novel processes of making the same. The invention isconcerned with compounds which are structurally related to certaintricyclic heterocycles having a single heterocyclic nitrogen, oxygen orsulfur atom: specifically, the heterocycles referred to are acridine,xanthene and thiaxanthene. In the present disclosure, the termsacridine, Xanthene and thiaxanthene' are used in the same sense asindicated for each term, respectively, under Nos. 1973, 2000 and 2019 inThe Ring Index by Patterson and Capell (New York, N. Y., 1940); and thenum bering systems herein employed to identify the compounds of theinvention, related to acridine, xanthene or thiaxantheme as the case maybe, are the preferred numbering systems indicated by The Ring Indexunder the serial numbers above cited.

More particularly, the invention relates to compounds selected from theclass consisting of bases having the formula l I R R In the case of thexanthene derivatives, the compounds of the invention can becharacterized as comprising the 9- xanthone nucleus of Formula IIIbelow, wherein is substituted a basic ether radical R as defined above:

2 In the case of the thiaxanthene derivatives, the compounds of theinvention can be characterized as comprising the 10- thiaxanthonenucleus of Formula IV below, wherein is substituted a basic etherradical R as defined above:

3 l1o 7 \g It will be observed that the numbering plan for thethiaxanthone nucleus difiers somewhat from those for the acridone andXanthone nuclei, respectively; in agreement with the preferred numberingsystems employed by The Ring Index.

In the compounds of the invention represented by Formula I above, atleast one but not more than two of the radicals R attached to thearomatic rings is a di(lower alkyl)amino(lower alkoxy) radical, e. g.dimethylaminomethoxy, dimethylaminoethoxy, diethylaminoethoxy,dimethylamino(n-propoxy), diethylaminoisopropoxy, di-(sec-heXyDaminoethoxy, and the like. The remaining radicals R are eitherhydrogen or lower alkyl radicals, e. g. methyl, ethyl, n-propyl, isoamyland the like, and these radicals R need not be identical.

Compounds of the invention represented by Formula I above are strongbases, and readily form acid addition salts with inorganic and organicacids, e. g. hydrochloric, hydrobromic, hydriodic, sulfuric, phosphoric,acetic, tartaric, oxalic, citric and ethanesulfonic acids, and the like;and also form quaternary ammonium salts with acyclic and cyclicquaternizing agents, such as lower alkyl halides (e. g. methyl bromide,ethyl iodide, n-butyl chloride), di(lower alkyl)sulfates (e. g.dimethylsulfate), benzyl halides (e. g. benzyl bromide), and the like.Since the bases of Formula I may be monoacidic or polyacidic bases, thesalts formed by these bases include the monoand poly-acid additionsalts, and similarly monoand poly-quaternary salts. The inventionincludes not only the bases of Formula I above but also all the acidaddition salts and quaternary salts of said bases. A particularlypreferred class or" salts is those formed by the bases with thenon-toxic acids and quaternizing agents conventionally employed in thepreparation of chemotherapeutic substances. The bases of Formula I aboveand their salts are useful as chemotherapeutic agents, e. g. asanthelmintic agents (for instance in combatting pinworms as exemplifiedby Syphacz'a obvelata); and as antifungal agents (for instance incombatting Trichophyton mentagrophytes and Microsporon lanosum). Theacridones are also useful as antitrypanosomal agents (for instance incombatting Trypanosoma equiperdum).

A general method for preparing the compounds of Formula I abovecomprises reacting a compound of the formula wherein Z has the samemeaning indicated above; and R is a monovalent radical selected from thegroup consisting of hydrogen, lower alkyl and hydroxyl; at least one butnot more than two of the radicals R being a hydroxyl radical with adi(lower alkyl)amino(lower alkyl) halide in the presence of an acidacceptor; e. g. by heating the reactant of Formula V together with thehalide reactant in an inert organic solvent, in the presence of analkali metal lower alkoxide. From the bases of Formula I, the acidaddition salts and quaternary salts of the in vention can be prepared,e. g. by heating the base with the appropriate acid or quaternizingagent, respectively.

The invention is further disclosed in the following examples, which areillustrative but not limitative thereof.

Example 1 38.5 g. of 4-hydroxy-9(10H)-acridone, 400 cc. ofchlorobenzene, 12g. of sodium methoxide and 50 cc. of methanol werestirred and heated to distil off methanol, until the temperature of thereaction mass reached 130 C. The reaction mixture was then cooled to 100C. and 30g. of ,B-diethylaminoethyl chloride was added. The mixture wasthen stirred and refluxed for four hours. 250 cc. of water and 10 cc. of40 per cent sodium hydroxide solution were added at 100 C., and thestirring was continued for an additional half hour. The reaction mixturewas then allowed to stratify, and the chlorobenzene layer was taken off,dried over sodium sulfate, and concentrated in vacuo. The residual oilwas digested with ether, and the crystalline product which separated wasrecrystallized from a mixture of benzene and petroleum ether. The4-(B-diethylaminoethoxy)9(10H)- acridone thus obtained was a tan solid,of melting point 62 C., insoluble in water, but soluble in acids, e. g.normal hydrochloric acid, normal sulfuric acid, acetic acid andpropionic acid.

The dihydrochloride of the above base was prepared by dissolving 5 g. ofthe recrystallized tan solid of M. P. 62 C. in 75 cc. of acetone, andadding to the solution, at C., cc. of 35 per cent ethanolic hydrogenchloride. The 4-(fl-diethylaminoethoxy)-9(10H)-acridone dihydrochloridethus obtained was a light yellow powder, M. P. 236238 C. afterrecrystallization from acetone. It was soluble in water.

A methyl bromide quaternary salt of the above base was prepared bydissolving 6 g. of the recrystallized base of M. P. 62 C. in 35 cc. ofacetone, filtering, and adding to the filtrate 10 cc. of a 23 per centw./v. solution of methyl bromide in acetone. The mixture was allowed tostand 48 hours in the refrigerator, whereupon 4-(5- diethylaminoethoxy)9(10H) acridone methobromide crystallized, M. P. 229-230 C. This saltwas soluble in water.

Example 2 29 g. of 2-hydroxy-9(10H)-acridone, 350 cc. of chlorobenzene,10 g. of sodium methoxide and 50 cc. of methanol were stirred and heatedto distil off the methanol as in Example 1. The sodium salt of thehydroxyacridone thus obtained was condensed with 25 g. ofdiethylaminoethyl chloride in the same manner as described in Example 1,and crystalline condensation product was likewise recovered in the samemanner as described in that example. The2-({3-diethylaminoethoxy)-9(10H)- acridone thus obtained, slightlyyellow crystals after recrystallization from chlorobenzene, had M. P.209-2ll C. The product was insoluble in water but slightly soluble inalcohol.

By dissolving the above base in methanol and adding ethanolic hydrogenchloride, the dihydrochloride was obtained: yellow crystals, M. P. 183C. with decomposition, after recrystallization from a mixture ofmethanol and acetone. This salt was soluble in water.

Example 3 32 g. of l-methyl-4-hydroxy-9(10H)acridone, 10 g. of sodiummethylate, 350 cc. of chlorobenzene and 50 cc. of methanol, were reactedto form the sodium salt of the acridone as in Example 1. The reactionmixture 4 was cooled to about 100 C. and reacted with 25 g. ofB-diethylaminoethyl chloride. The condensation product was recovered asin Example 1, and recrystallized from ether and then from alcohol. Thetan material thus obtained, 1methyl-4-(fi-diethylaminoethoxy) 9 10H)acridone, M. P. 147l48 C., was insoluble in water.

A soluble hydrochloride was prepared by dissolving the base in methanoland passing hydrogen chloride gas into the solution, with cooling, untilsaturation. Upon addition of ether, a dihydrochloride of yellowish colorprecipitated. Upon recrystallization from percent ethanol, and drying inthe oven at 95 C., the dihydrochloride lost one mol of HCl. Theresulting monohydrochloride melted at 234236 C.

Example 4 25 g. of 4-hydroxy-9-xanthone, 10 g. of sodium methoxide, 300cc. of chlorobenzene and 40 cc. of methanol were stirred and heated insuch a way that the methanol was allowed to distil off until thereaction mixture reached a temperature of 130 C. The mixture was thencooled to about C. and 25 g. of fi-diethylaminoethyl chloride wereadded. The mass was stirred and refluxed at C. for 5 hours and thencooled to 100 C. 250 cc. of water and 10 cc. of 40 per cent sodiumhydroxide solution were added and the mixture was stirred for anadditional hour. The mixture was allowed to stratify into layers; thechlorobenzene layer was taken off, dried over sodium sulfate andconcentrated in vacuo. The residual oil was dissolved in ether, cooledto 5 C. and reacted with 25 cc. of 35 per cent ethanolic hydrogenchloride. The crude hydrochloride thus precipitated was recrystallizedfrom alcohol. The resulting white crystalline 4-(;9-diethylaminoethoxy)9-xanthone hydrochloride melted at 236 C. It wassoluble in water.

Example 5 25 g. of 2-hydroxy-9-xanthone, 10 g. of sodium methoxide, 300cc. of chlorobenzene, 40 cc. of methanol and 25 g. of,B-diethylaminoethyl chloride were reacted in the same way as describedin Example 4. After recrystallization from ethanol, the2-(fi-diethylaminoethoxy-Q- xanthone hydrochloride had M. P. of 194195C. This product was a white crystalline materal soluble in water.

Example 6 23 g. of 2,7-dihydroxy-9-xanthone, 16 g. of sodium methoxide,350 cc. of chlorobenzene and 60 cc. of methanol were reacted to form thedisodium salt, in the same manner described in Example 4. The disodiumsalt thus obtained was condensed with 33 g. of fi-diethylaminoethylchloride by refluxing the reaction mixture for 5 hours at 130 C. Thereaction mixture was then cooled to 100 C., and 300 cc. of water and 10cc. of 40 per cent sodium hydroxide solution were added, and the wholestirred for /2 hour. The mixture was allowed to stratify, thechlorobenzene layer was separated and dried over sodium sulfate andconcentrated in vacuo. The residual oil was dissolved in 300 cc. ofether, filtered, the filtrate was chilled to 5 C. and precipitated with30 cc. of 35 per cent ethanolic hydrogen chloride. The2,7-bis(fl-diethylaminoethoxy)9 xanthone dihydrochloride thus obtainedwas recrystallized from methanol, M. P. 229 C. It was a whitecrystalline material soluble in water.

Example 7 30 g. of 4-methyl-8-hydroxy-lO-thiaxanthone, 10 g. of sodiummethoxide, 350 cc. of chlorobenzene, and 50 cc. of methanol were stirredand heated to a temperature of 130 C., a portion of the methanoldistilling off in the meantime. The reaction mixture was then cooled to100 C., and 27 g. of [B-diethylaminoethyl chloride was added, and themixture was then stirred and refluxed for 4 hours. At the end of thistime, the reaction mixture was cooled to 100 C. and 250 cc. of water and10 cc. of 40 per cent sodium hydroxide solution were added, and stirringwas continued for /2 hour longer. The chlorobenzene layer was thenseparated and dried over sodium sulfate and concentrated in vacuo. Theresidual oil was dissolved in 300 cc. of ether, and to the solution wereadded 20 cc. of 35 per cent ethanolic hydrogen chloride. The resulting4-methyl-8-(B-diethylaminoethoxy)-10 thiaxanthone hydrochloride wasrecrystallized from a mixture of acetone and alcohol: slightly yellowcrystals, M. P. 212-214" C., soluble in water and in alcohol.

I claim:

1. A compound selected from the class consisting of bases having theformula wherein Z is a bivalent radical selected from the groupconsisting of imino, 0x0 and thio, and each R is a monovalent radicalselected from the group consisting of hydro- 25 gen, lower alkyl anddi(lower alkyl) amino(lower alkoxy);

at least onebut not more than two of the radicals R being a di(loweralkyl)amino(lower alkoxy) radical and salts of said bases.

2. A monosubstituted 9(10H)-acridone wherein the sole substituent is adi(lower alkyl)amino(lower alkoxy) radical attached to a nuclear carbonatom.

3. A monosubstituted 9-xanthone wherein the sole substituent is adi(lower alkyl)amino(lower alkoxy) radical attached to a nuclear carbonatom.

4. A monosubstituted IO-thiaxanthone wherein the sole substituent is adi(lower alkyl)amino(lower alkoxy) radical attached to a nuclear carbonatom.

5. A disubstituted 9(10H)-acridone wherein the two substituents are (1)a di(lower alkyl)amino(lower alkoxy) radical and (2) a lower alkylradical, each substituent being attached to a separate nuclear carbonatom.

6. Acid addition salts of the compounds of claim 5.

7. l-methyl 4 (B diethylaminoethoxy) 9(10H)- acridone.

8. 1 methyl 4 (p diethylaminoethoxy) 9(10H)- acridone hydrochloride.

References Cited in the file of this patent FOREIGN PATENTS 490,418Germany Jan. 9, 1930

1. A COMPOUND SELECTED FROM THE CLASS CONSISTING BASES HAVING THEFORMULA